The present invention concerns taxoid conjugates, pharmaceutical formulations containing the same, and methods of use thereof as antimitotic and antitumor agents, particularly for the treatment of tumors such as breast cancer and ovarian cancer.
The complex diterpenoid paclitaxel (1) is an exciting new anticancer drug, which is currently in clinical use against ovarian and breast cancer under the trademark TAXOL(copyright). See generally Merck Index, Monograph No. 7117 (12th Ed. 1996).
Paclitaxel acts by an unusual mechanism: promoting microtubule assembly. Since the discovery of paclitaxel as an antimitotic antitumor agent, its chemistry and structure activity relationship have been extensively studied in order to develop more potent derivatives and to overcome its low water solubility and drug resistance problems. Much research has focused on the modifications at C2, C4, C7, C9, C10, and the C13 side chain, and the resulting structure-activity relationships have led to more potent paclitaxel derivatives. Also, selective modification of the 2xe2x80x2-hydroxyl led to synthesis of a series of water-soluble derivatives (A. Mathew et al., J Med. Chem. 1992, 35, 145-151). However, drug resistance is still a major problem associated with paclitaxel, and novel derivatives are highly desirable.
Previously, we synthesized and evaluated two compounds (3 and 4) that are conjugates of a camptothecin (CPT) derivative and an etoposide (5) analog (K. Bastow et al., Bioorg. Med Chem. 1997, 5, 1481-1488). Both compounds induced protein-linked DNA breaks (PLDB) in a concentration dependent manner in drug treated cells. The drug induced PLDB could be mediated by both DNA topoisomerases (topo) I and II. The two conjugates were more active than CPT against CPT-resistant cells and than etoposide against etoposide-resistant cells. Over-expression of the multiple drug resistant proteins GP 170 or MRP had little impact on the cytotoxicity. The compounds were equally cytotoxic as CPT in CPT-sensitive or etoposide-resistant cells and as etoposide in CPT-resistant cells. In vivo, one conjugate (3) was more active than either etoposide or CPT against human KB and DU-145 tumor cells in nude mice. This topo I and II dual inhibitory property as well as the unique antitumor action of these CPT-etoposide analog conjugates suggests that such bimolecular models should be further explored as anticancer drugs.
A first aspect of the present invention is a compound according to formula I:
T1xe2x80x94Lxe2x80x94T2xe2x80x83xe2x80x83(1)
wherein:
T1 is a taxoid group, preferably of Formula II: 
xe2x80x83wherein R1 is C6H5, and R2 is O;
L is a linking group; and
T2 is a substituent selected from the group consisting of epipodophyllotoxin, amsacrine, ellipticine, anthracycline antibiotic, mitoxantrone, mitomycin, quinolone, and colchicine groups;
or a pharmaceutically acceptable salt thereof.
A second aspect of the present invention is a pharmaceutical formulation comprising a compound according to Formula I above in a pharmaceutically acceptable carrier.
A further aspect of the present invention is a method of treating a tumor, particularly a solid tumor, comprising administering to a subject in need thereof a treatment effective amount of a compound according to Formula I above. Examples of tumors that may be treated include, but are not limited to, lung cancer, colon cancer, central nervous system cancers, melanoma, ovarian cancer, prostate cancer and breast cancer tumors.
A further aspect of the present invention is a method of treating cancer in a subject in need thereof, the method comprising administering to the subject an effective cancer treating amount of a compound according to Formula I. Illustrative cancers that may be treated by the present invention include, but are not limited to, small cell lung cancer, testicular cancer, lymphoma, leukemia, esophageal cancer, stomach cancer, colon cancer, breast cancer, central nervous system cancer, liver cancer and prostate cancer.
A further aspect of the present invention is a method of inducing cellular differentiation, the method comprising contacting (in vivo or in vitro) a cancer cell with a differentiation effective amount of a compound according to Formula I above.
A further aspect of the present invention is method of inhibiting cellular mitosis, comprising contacting (in vivo or in vitro) a cell with a mitosis inhibiting amount of a compound according to Formula I above.